The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. The human cornea has several layers. The outermost layer is the corneal epithelium, an exceedingly thin multicellular epithelial tissue layer (non-keratinized stratified squamous epithelium) of fast-growing and easily regenerated cells, kept moist with tears. Irregularity or edema of the corneal epithelium disrupts the smoothness of the air/tear-film interface, the most significant component of the total refractive power of the eye, thereby reducing visual acuity. It is continuous with the conjunctival epithelium, and is composed of several layers of cells which are shed constantly on the exposed layer and are regenerated by multiplication in the basal layer.
The conjunctiva lines the inside of the eyelids and covers the sclera. It is composed of non-keratinized, stratified columnar epithelium with goblet cells, and also stratified columnar epithelium. The conjunctiva helps lubricate the eye by producing mucus and tears, although a smaller volume of tears than the lacrimal gland. It also contributes to immune surveillance and helps to prevent the entrance of microbes into the eye.
The tear film coating the eye, known as the precorneal film, has three distinct layers, from the most outer surface: lipid layer, aqueous layer and mucous layer. The mucus layer coats the cornea, provides a hydrophilic layer and allows for even distribution of the tear film. The mucins present in the tear film serve to maintain the hydration of the ocular surface and to provide lubrication and anti-adhesive properties between the cells of the ocular surface and conjunctiva during the blink and to contribute to the epithelial barrier to prevent pathogens from binding to the ocular surface.
Disorders of the conjunctiva and cornea are a common source of eye complaints since the surface of the eye is exposed to various external influences and is especially susceptible to trauma, infections, chemical irritation, allergic reactions and dryness.
Re-epithelization of the conjunctiva and/or cornea and/or increase in mucin production, in particular MUC1 and MUC5AC, are strategies for the management of several ocular diseases, such as dry eye (including keratoconjunctivitis sicca, xerophthalmia, xerosis and Sjögren's syndrome), conjunctivitis (including allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, pemphigoid, Stevens-Johnson syndrome, toxic epidermal necrolysis, viral keratoconjunctivitis and limbic keratoconjunctivitis), dermatitis (including contact dermatitis, atopic dermatitis), blepharitis (including chronic anterior blepharitis, chronic posterior blepharitis), entropion (including paralytic entropion, involutional entropion), floppy eyelid syndrome, thyroid ophthalmopathy, pterygium, conjunctivochalasis, epithelial damage induced by preservatives, epithelial or anterior chamber damage induced by ocular surgery, limbal cell deficiency, corneal ulcers induced by physical or chemical agents, keratitis (including Stromal necrotic keratitis, Cogan's syndrome, Mooren's ulcer, neurotrophic keratitis, exposure keratitis, crystalline infectious keratitis, Thygeson's superficial punctate keratitis, filamentary keratitis, recurring corneal epithelial erosions, epithelial dystrophies and Meesmann's dystrophy), episcleritis and uveitis.
Dry eye is a common disorder provoking changes in tear film and ocular surface. Dry eye occurs when the eye does not produce tears properly, or when the tears are not of the correct consistency and evaporate too quickly. Untreated dry eye can cause ocular infections, corneal ulcer and blindness [Colligris et al., Exper Opin Pharmacother. 2014, 15, 1371-1390]. The term dry eye is used in the present invention to encompass keratoconjunctivitis sicca, xerophthalmia, xerosis and Sjögren's syndrome. A therapeutic approach for the treatment of dry eye is healing of the injured corneal epithelium [Versura et al., Cornea. 2013, 32, 412-418]. Moreover, ocular mucin expression levels, in particular MUC1, MUC2, MUC4 and MUC5AC, have been reported to be significantly lower in patients with dry eye syndrome [Corrales et al., Invest Ophthalmol Vis Sci. 2011, 52, 8363-8369; Uchino et al., JAMA Ophthalmol. 2014, 132, 985-992]. Thus, promoting mucin production, in particular MUC5AC, is also a promising therapeutic approach for managing dry eye. Examples of this treatment route is described in Toda et al., Amer. J. Ophthalmology. 2014, 157, 616-622 and Arakaki et al., PLOS One, 2014, 9(5), e98390(1-7). Moreover, lubrication of the surface of the eye and helping tears to remain on the surface of the eye improves the symptoms of dry eye. Thus, artificial tear formulations, such as lipid-based artificial tear formulations comprising either castor oil or a medium chain triglyceride, have been disclosed for the treatment of dry eye disease [Simmons et al., Clinical Therapeutics. 2015, 37, 858-868; Hasegawa et al., J Vet Med Sci., 2014, 76, 1219-1224; Kaercher et al., Clinical Ophthalmology. 2014, 8, 1147-1155; Zhang et al., Nanothecnology. 2014, 25, 125101; Maïssa et al., Contact Lens Anterior Eye. 2010, 33, 76-82; Khanal et al., Cornea. 2007, 26, 175-181; Mohan et al., Int J Pharm Bio Sci. 2012, 3, 1-13; WO 2014/153733 A1; WO 2013/086449 A1; WO 2013/086438 A1; WO 2010/141648 A2].
Conjunctivitis is a common condition that causes redness and inflammation of the conjunctiva. The term conjunctivitis is used in the present invention to encompass allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, pemphigoid, Stevens-Johnson syndrome, toxic epidermal necrolysis, viral keratoconjunctivitis and limbic keratoconjunctivitis. Allergic conjunctivitis (which is caused by an allergic reaction to a substance such as pollen or dust mites) and vernal keratoconjuctivitis (allergic eye disease that especially affects young boys) may produce corneal lesions [Mimura et al., Curr Eye Res. 2012, 37, 864-870; Miyoshi et al., Cornea. 2001, 20, 743-747]. Atopic keratoconjuctivitis (which is a chronic allergic ocular disease that occurs most often in patients with a history of atopic dermatitis) is characterized by alterations of mucin expression, in particular MUC16 and MUC5AC. Mantelli et al., Curr Opin Allergy Clin Immuniol. 2008, 8(5), 477-483 reports that in patients with vernal keratoconjuctivitis successful treatment with anti-allergic and anti-inflammatory drugs was associated with increased MUC5AC expression which was decreased in patient suffering from the disease. Kardon et. al. Investigative Ophthalmology & Visual Science, 1999, 40(7), 1328-1335 reports that loss of MUC1 functional protein via homologous recombination leads to an increase in the frequency and severity of conjunctivitis and blepharitis in mice. Thus, re-epithelization and promoting mucin expression, in particular MUC5AC, are key factors in the treatment of these diseases. At present, common treatments of conjunctivitis include ophthalmic compositions comprising antibiotics, antihistamines or steroids.
Benzalkonium chloride (BAK), the preservative most frequently used in eyedrops, has demonstrated its toxic effect in laboratory, experimental and clinical studies. It has been shown to cause disruption of the corneal epithelium barrier [Baudouin et al., Prog Retin Eye Res. 2010, 29m 312-334; Barabino et al., Invest Ophthalmol Vis Sci. 2014, 55, 6499-6504; Liu et al., Chin Med J., 2015, 128, 2444-2449]. Dorennavar et al., Indian J. Clin. and Exper. Ophthalmology, 2015; 1(4):191-196 discloses that rebapamide, a drug which increases mucin production mediated by MUC1 and MUC4 gene expression, is useful in the treatment of dry eye syndrome (caused among others by preservatives present in tear substitutes like benzalkonium chloride, sodium perborate sodium chloride), ocular surface disorders and allergic conjunctivitis. Moreover, goblet cells, which produce MUC5AC, are reduced by treatment with BAK [Barabino et al., Invest Ophthalmol Vis Sci. 2014, 55, 6499-6504]. MUC5AC is a gel-forming secretory mucin. Secretion typically occurs in response to a stimulus, such as a foreign body on the ocular surface. Thus, promoting re-epithelization and mucin production is a promising strategy for managing the damage induced by preservatives.
Ocular surgery, such as photorefractive keratectomy and laser in situ keratomileusis, produces corneal epithelial damage since it compromises corneal barrier function, tear film stability and corneal sensation [Nejima et al., Am J Ophthalmol. 2005, 139, 64-71; Chen et al. J Refract Surg. 2007, 23, 916-923]. Cataract surgery does also damage the ocular surface and decreases goblet cell density [Oh et al., Jpn J Ophthalmol. 2012, 56, 113-118; Ke et al., Yonsei Med J. 20014, 55, 197-202]. Lee et al. J. Ophthalmol. 2016, 2016, ID 8150757 shows that stimulation of mucin secretion using Diquafosol is a successful strategy to treat dry eye after cataract surgery. Similarly, Mori et al. Cornea, 2014, 33(7), 659-662 described that diquafosol treatment increases mucin production and improves the subjective and objective symptoms of persistent dry eye after LASIK. Thus, promoting corneal re-epithelization and mucin production, in particular MUC5AC, allows managing epithelial or anterior chamber damage induced by ocular surgical procedures.
Limbal cell deficiency is characterized by a loss or deficiency of the cells in the limbus that are vital for re-population of the corneal epithelium and to the barrier function of the limbus. When these cells are lost, the corneal epithelium is unable to repair and renew itself. This results in epithelial breakdown and persistent epithelial defects, corneal conjunctivalization and neovascularization, corneal scarring, and chronic inflammation. All of these contribute to loss of corneal clarity, potential vision loss, chronic pain, photophobia, and keratoplasty failure. Optimization of ocular surface health is the first step in the management of limbal cell deficiency. Often, there are constant insults to the corneal epithelium from multiple concurrent external disorders such as dry eyes, ocular surface inflammation, soft contact lens, and drug toxicity from multiple eye medications. Improving ocular surface health provides a better environment for the remaining limbal cells to survive. Promoting corneal re-epithelization is thus useful for the managing limbal cell deficiency [Wan et al., Invest Ophtalmol Vis Sci. 2011, 52, 724-730; Tsai et al., N Engl J Med. 2000, 343, 86-93; Sehic et al., J Funct Biomater. 2015, 6, 863-888]. At present, this is achieved by administration of preservative-free artificial tears, punctual occlusion, topical cyclosporine, preservative free topical cortical steroids or surgery.
Traumatic corneal ulcers, such as those induced by physical agents, contact lenses or chemical agents, are healed by corneal re-epithelization [Scardovi et al., Ophthalmologica. 1993, 206, 119-124; Salman et al., Cutan Ocul Toxicol. 2010, 29, 116-121; Wipperman et al., Am Fam Physician. 2013, 87, 114-120]. It has also been disclosed that MUC5AC expression is significantly lower in eyes with corneal ulcers [Dogru et al., Curr Eye Res. 2005, 30, 897-908]. Moreover, goblet cells, which produce MUC5AC, are lost in alkali burns. Thus, promoting corneal re-epithelization and mucin production, in particular MUC5AC, is useful for the treatment of corneal ulcers, such as those induced by physical or chemical agents. At present, corneal ulcer treatment typically involves the use of topical antibiotics or even surgery.
Keratitis is an inflammation of the cornea which may be caused by an infection involving bacteria, viruses, fungi or parasites, or by a minor injury produced, for example, by wearing contact lenses too long. The term keratitis is used in the present invention to encompass Stromal necrotic keratitis, Cogan's syndrome, Mooren's ulcer, neurotrophic keratitis, exposure keratitis, crystalline infectious keratitis, Thygeson's superficial punctate keratitis, filamentary keratitis, recurring corneal epithelial erosions, epithelial dystrophies and Meesmann's dystrophy. O'Brien et. al., Arch Ophthalmol. 1995; 113, 1257-1265 describes that re-epithelization is a relevant end point in evaluating the healing of ulcerous keratitis. Albietz et. al., Optom Vis Sci. 2003, 80, 420-430 informs that patients suffering from filamentary keratitis show a reduced goblet cell density and that filamentary keratitis is a condition associated with aqueous-deficient dry eye (keratoconjunctivitis sicca). Thus, promoting corneal re-epithelization and/or mucin production, in particular MUC5AC, allows managing keratitis. At present, keratitis is treated antibacterial, antifungal, or antiviral therapy, steroid drops or wetting drops.
Uveitis is the inflammation of the uvea, the pigmented layer that lies between the inner retina and the outer fibrous layer composed of the sclera and cornea. Thus, promoting corneal re-epithelization and/or mucin production, in particular MUC5AC, allows managing keratitis. Uveitis is typically treated with glucocorticoid steroids.
Dermatitis is inflammation of the skin. Examples of dermatitis are contact dermatitis and atopic dermatitis.
Blepharitis is an eye condition characterized by chronic inflammation of the eyelid. Examples of blepharitis are chronic anterior blepharitis and chronic posterior blepharitis. Kardon et. al. Investigative Ophthalmology & Visual Science, 1999, 40(7), 1328-1335 reports that loss of MUC1 functional protein via homologous recombination leads to an increase in the frequency and severity of conjunctivitis and blepharitis in mice. Thus, increasing the expression of MUC1 appears to be a valuable strategy in the treatment of blepharitis.
Entropion is a medical condition in which the eyelid (usually the lower lid) folds inward. It is very uncomfortable, as the eyelashes constantly rub against the cornea and irritate it. Examples of entropion are paralytic entropion and involutional entropion.
Floppy eyelid syndrome is a disease whose most prominent features often include floppy upper eyelids that can be easily everted, as well as papillary conjunctivitis.
Thyroid ophthalmopathy, also known as Graves' ophthalmopathy, is an autoimmune inflammatory disorder affecting the orbit around the eye, characterized by upper eyelid retraction, lid lag, swelling (edema), redness (erythema), conjunctivitis, and bulging eyes (proptosis).
There is a need in the art for alternative treatments for managing ocular diseases, in which re-epithelization and/or mucin production, in particular MUC1 and MUC5AC, are involved, such as dry eye (including keratoconjunctivitis sicca, xerophthalmia, xerosis and Sjögren's syndrome), conjunctivitis (including allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, pemphigoid, Stevens-Johnson syndrome, toxic epidermal necrolysis, viral keratoconjunctivitis and limbic keratoconjunctivitis), dermatitis (including contact dermatitis, atopic dermatitis), blepharitis (including chronic anterior blepharitis, chronic posterior blepharitis), entropion (including paralytic entropion, involutional entropion), floppy eyelid syndrome, thyroid ophthalmopathy, pterygium, conjunctivochalasis, epithelial damage induced by preservatives, epithelial or anterior chamber damage induced by ocular surgery, limbal cell deficiency, corneal ulcers induced by physical or chemical agents, keratitis (including Stromal necrotic keratitis, Cogan's syndrome, Mooren's ulcer, neurotrophic keratitis, exposure keratitis, crystalline infectious keratitis, Thygeson's superficial punctate keratitis, filamentary keratitis, recurring corneal epithelial erosions, epithelial dystrophies and Meesmann's dystrophy), episcleritis and uveitis, more particularly in the treatment and/or prevention of dry eye, blepharitis, keratitis such as filamentary keratitis and ulcerous keratitis, conjunctivitis including atopic keratoconjunctivitis, epithelial damage induced by preservatives, epithelial or anterior chamber damage induced by ocular surgery, limbal cell deficiency, corneal ulcers induced by physical or chemical agents.